1. Clinical Research in Hematology • Vol 3 • Issue 1 • 2020 8
INTRODUCTION
H
yponatremia is a common electrolyte abnormality in
hospitalized patients, with a widely varying incidence
of 15–45%.[1-4]
Although this complication has been
reported with various infectious diseases and cardiovascular
events, many reports have also described hyponatremia in
association with chemotherapy, particularly with platinum
agents.[5-7]
The alkylating agent cyclophosphamide (CPM) is a key
drug in the treatment of malignant lymphoma (ML).
As adverse events, bone marrow suppression, infection,
hemorrhagic cystitis, and secondary malignancies are well
known.[8]
Although the syndrome of inappropriate secretion
of antidiuretic hormone (SIADH)[9,10]
is known as a rare
adverse event that induces severe hyponatremia, studies
remain limited to a few case reports, and the incidence of this
complication remains unclear.[11-15]
Here, we report the incidence of hyponatremia among
hospitalized patients treated with CPM for ML patients in a
single-center and retrospective study.
Hyponatremia Caused by Cyclophosphamide-
containing Chemotherapy for Malignant Lymphoma
Patients: A Single-center and Retrospective Study
Junji Hiraga1
, Yasuhiko Harada1
, Naruko Suzuki1
, Natsuko Uematsu2
, Yoshitoyo Kagami1
1
Department of Hematology, Toyota Kosei Hospital, Toyota, Japan, 2
Department of Pharmacology, Toyota Kosei
Hospital, Toyota, Japan
ABSTRACT
Objective: Cyclophosphamide (CPM) is a key chemotherapeutic drug for malignant lymphoma (ML). Hyponatremia
caused by CPM is a rare but severe adverse event. We studied the incidence of hyponatremia among hospitalized patients
treated with CPM for ML patients in a single-center and retrospective study. Patients and Methods: This study investigated
a total of 832 cases (367 patients) of chemotherapy, including intravenous CPM administration during hospitalization in
our institute with ML between April 2009 and December 2019. Median age was 67 years (range, 18–91 years), with 210
men (456 cases, 54.8%). Diffuse large B-cell lymphoma was the most common type of ML treated (60.2%). Hyponatremia
severity was defined according to the Common Terminology Criteria for Adverse Events version 5.0. We analyzed variables
known to be associated with hyponatremia. Results: Of the 761 cases without hyponatremia before CPM administration, 82
cases (10.8%) developed hyponatremia after CPM administration. High-dose CPM administrations correlated significantly
with hyponatremia (P 0.001). After analysis of other variables, the complication of vomiting (P 0.001) and use of a
selective serotonin reuptake inhibitor (P 0.001) showed a significant correlation with hyponatremia. Conclusion: The
incidence of hyponatremia after chemotherapy, including CPM was high, particularly with high-dose chemotherapy. After
CPM administration, close monitoring is warranted to prevent hyponatremia.
Key words: Cyclophosphamide, hyponatremia, malignant lymphoma, syndrome of inappropriate secretion of antidiuretic
hormone
ORIGINAL ARTICLE
Address for correspondence:
Junji Hiraga, Department of Hematology, Toyota Kosei Hospital, 500-1, Ibobara, Josui-cho, Toyota City 470-0396, Japan.
Tel: 81-565-43-5000; Fax: 81-565-43-5100.
https://doi.org/10.33309/2639-8354.030102 www.asclepiusopen.com
© 2020 The Author(s). This open access article is distributed under a Creative Commons Attribution (CC-BY) 4.0 license.

2. Hiraga, et al.: Hyponatremia caused by cyclophosphamide-containing chemotherapy
Clinical Research in Hematology • Vol 3 • Issue 1 • 2020
PATIENTS AND METHODS
We retrospectively analyzed the clinical records of 367
patients (administration of 832 cases) with ML admitted to
Toyota Kosei Hospital to receive chemotherapy that included
CPM infusion between April 2009 and December 2019. All
patients had undergone a measurement of serum sodium levels
before and after chemotherapy. Median age was 67 years
(range, 18–91 years), with 210 men (456 cases, 54.8%). Cases
were divided into three groups according to the dose of CPM
administered. CPM doses were 30 mg/kg/day in 691 cases
(357 patients), with typical chemotherapy regimens, including
CHOP therapy (CPM, doxorubicin [DXR], vincristine
[VCR], and prednisolone), EPOCH therapy (etoposide
[ETP], prednisolone, VCR, CPM, and DXR), or hyper-CVAD
therapy (CPM, VCR, DXR, and dexamethasone). CPM doses
were 30–49 mg/kg/day in 117 cases (46 patients), and the
main treatment regimen was CHASE therapy (CPM, high-
dose cytarabine, dexamethasone, and ETP). CPM doses were
≥50 mg/kg/day in 24 cases (24 patients), as pretreatment for
autologous peripheral blood stem cell transplantation using
LEED therapy (melphalan, CPM, ETP, and dexamethasone).
Hyponatremia severity was defined according to the Common
Terminology Criteria for Adverse Events version 5.0:[16]
Grade 1,130–135 mmol/L; Grade 2, 125–129 mmol/L
and asymptomatic; Grade 3, 125–129 mmol/L symptoms
or 120–124 mmol/L regardless of symptoms; Grade
4,120 mmol/L, life-threatening consequences; or Grade
5, death. We analyzed variables known to be associated
with hyponatremia, age, sex, pathologically diagnosed
diffuse large B-cell lymphoma (DLBCL) and others, CPM
dose, complications of elevated serum creatinine before
treatment, vomiting as a complication, death within 3 months
after treatment, administration of VCR, development of
pneumonia before CPM, use of a selective serotonin reuptake
inhibitor (SSRI), total daily amount of free water intravenous
fluid, and total daily amount of sodium by intravenous drip
infusion.[9,10]
The Chi-square test and t-test were used to
compare categorical variables and Fisher’s exact test for
comparison between two groups. Logistic regression analysis
was used for multivariate analysis. Statistical analysis was
performed using JMP version 11 software (SAS Institute,
Cary, North Carolina, USA).
RESULTS
In all 832 cases, the most common pathological subtype
of ML being treated was DLBCL (60.2%). With 71 cases
(8.53%), the patients showed hyponatremia before CPM-
containing chemotherapy, comprising Grade 1 in 56 cases,
Grade 2 in 8 cases, Grade 3 in 6 cases, and Grade 4 in 1 case.
After CPM-containing chemotherapy, serum sodium level
normalized in 32 cases (45.1%).
Among the 761 cases without pretreatment hyponatremia, 82
(10.6%) developed hyponatremia after CPM administration
[Table 1], comprising Grade 1 in 68 cases, Grade 2 in 9 cases,
Grade 3 in 3 cases, and Grade 4 hyponatremia in 2 cases. In
the subgroups based on CPM dose, hyponatremia occurred
in 63 of 623 cases (10.1%) with CPM dose 30 mg/kg/day,
8 of 115 cases (7.0%) with CPM dose 30–49 mg/kg/day, and
11 of 23 cases (47.8%) with CPM dose ≥50 mg/kg/day. A
significant correlation was identified between high-dose
CPM and hyponatremia (P 0.001). After analysis of other
variables, the complication of vomiting (P 0.001) and use
of an SSRI (P 0.001) showed a significant correlation
with hyponatremia. No significant differences in age,
sex, diagnosis, complications of elevated creatinine
before treatment, death within 3 months after treatment,
administration of VCR, complication of pneumonia before
CPM, total daily amount of free water intravenous fluid, and
total daily amount of sodium by drip infusion. Two patients
who received high-dose CPM developed SIADH with grade
4 hyponatremia and required treatment in the intensive care
unit. Three other cases were diagnosed with SIADH. When
the multivariate analysis was performed using parameters
showing significant correlations on univariate analyses,
three variables displayed significant results: CPM dose
(P = 0.0115); vomiting as a complication (P = 0.0005); and
use of an SSRI (P = 0.0004).
DISCUSSION
In this study, 832 cases of chemotherapy, including
intravenous CPM administration, were administered to
hospitalized patients in our hospital. Hyponatremia was
observed with 71 cases before treatment with CPM, and
with 82 cases (10.8%) after treatment with CPM, and the
total rate of hyponatremia development was 18.4%. This was
comparable with findings from previous reports.[1-3]
Several
reports have described SIADH in ML patients and with the
use of SSRIs.[9,10]
When the CPM dose was 30 mg/kg/day, 63 (10.1%) of 623
patients developed hyponatremia. Similar doses of CPM are
usually administered as outpatient chemotherapy, and those
patients may also develop hyponatremia, but most do not
undergofollow-upofserumsodiumlevelsafterchemotherapy.
The hyponatremia caused by this dose was mostly Grade 1
and asymptomatic. With outpatient chemotherapy, the use of
drip infusion is transient, and this relatively limited use of a
drip may induce fluid restriction without inducing SIADH.[10]
Conversely, with doses ≥50 mg/kg/day, hyponatremia was
observed in 11 of 23 patients (47.8%). Two of the five patients
diagnosed with SIADH required treatment in the intensive
care unit. Careful attention should be paid to serum sodium
levels after high-dose CPM administration, particularly
among patients with vomiting or use of SSRIs.

3. Hiraga, et al.: Hyponatremia caused by cyclophosphamide-containing chemotherapy
Clinical Research in Hematology • Vol 3 • Issue 1 • 2020 10
Some limitations need to be considered when interpreting the
present results.Amounts of drinking water, food, urination, and
sodium in urine were not investigated in all cases, and this may
represent a limitation to the study. This reason may be why no
significant difference was found in the total daily amount of
free water administered intravenously or total daily amount of
sodium administered by drip infusion. Similarly, as the present
was a retrospective study, prospective studies may be required
to assess the incidence of hyponatremia more accurately.
CONCLUSION
The incidence of hyponatremia after chemotherapy, including
CPM, was high, at 10.8%. In particular, hyponatremia was
Table 1: Characteristics of patients without hyponatremia before CPM-containing chemotherapy
Hyponatremia Yes No P-value
82 679
Sex
Male 40 373
Female 42 306 0.292
Age
Median (range) 70 (26–87) 66 (18–91) 0.122
Diagnosis
DLBCL 54 401
Others 28 278 0.313
Amount of CPM
30 mg/kg/day 63 560
30–49 mg/kg/day 8 107
≥50 mg/kg/day 11 12 0.001
Elevated serum creatinine before treatment
Yes 7 59
No 75 620 0.963
Vomiting
Yes 18 34
No 64 645 0.001
Death within 3 months
Yes 6 26
No 76 653 0.151
VCR
Yes 61 515
No 21 164 0.858
Pneumonia
Yes 1 16
No 81 663 0.416
Use of SSRIs
Yes 9 10
No 73 669 0.001
Total daily amount of free water intravenously (mL)
Median (range) 1750 (600–4500) 1700 (400–5000) 0.126
Total daily amount of sodium(mmol/L)
Median (range) 153.9 (60–487) 142.4 (60.9–510.3) 0.371
CPM: Cyclophosphamide. DLBCL: Diffuse large B-cell lymphoma. SSRI: Selective serotonin reuptake inhibitor

4. Hiraga, et al.: Hyponatremia caused by cyclophosphamide-containing chemotherapy
Clinical Research in Hematology • Vol 3 • Issue 1 • 2020
frequently identified with high-dose chemotherapy. When
hyponatremia develops during CPM use, examination and
treatment with SIADH in mind should be performed as soon
as possible.
CONFLICTS OF INTEREST
The authors have no conflicts of interest to disclose.
REFERENCES
1. Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE. Impact
of hospital-associated hyponatremia on selected outcomes.
Arch Intern Med 2010;170:294-302.
2. Holland-Bill L, Christiansen CF, Heide-Jørgensen U,
Ulrichsen SP, Ring T, Jørgensen JO, et al. Hyponatremia
and mortality risk: A Danish cohort study of 279508 acutely
hospitalized patients. Eur J Endocrinol 2015;173:71-81.
3. Hao J, Li Y, Zhang X, Pang C, Wang Y, Nigwekar SU, et al.
The prevalence and mortality of hyponatremia is seriously
underestimated in Chinese general medical patients: An
observational retrospective study. BMC Nephrol 2017;18:328.
4. Kitchlu A, Rosner MH. Hyponatremia in patients with cancer.
Curr Opin Nephrol Hypertens 2019;28:433-40.
5. Berghmans T, Paesmans M, Body JJ. A prospective study
on hyponatremia in medical cancer patients: Epidemiology,
aetiology and differential diagnosis. Support Care Cancer
2000;8:192-7.
6. Ezoe Y, Mizusawa J, Katayama H, Kataoka K, Muto M.
An integrated analysis of hyponatremia in cancer patients
receiving platinum-based or nonplatinum-based chemotherapy
in clinical trials (JCOG1405-A). Oncotarget 2017;9:6595-606.
7. Shimada A, Takeuchi H, Fukuda K, Suda K, Nakamura R,
Wada N, et al. Hyponatremia in patients with esophageal cancer
treated with chemotherapy including cisplatin. Esophagus
2018;15:209-16.
8. Highlights of Prescribing Information These Highlights do Not
Include All the Information Needed to Use Cyclophosphamide
Safely and Effectively.Available from: https://www.accessdata.
fda.gov/drugsatfda_docs/label/2013/012141s090,012142s112
lbl.pdf. [Last accessed on 2020 Jun 01].
9. Hannon MJ, Thompson CJ. The syndrome of inappropriate
antidiuretic hormone: Prevalence, causes and consequences.
Eur J Endocrinol 2010;162:5-12.
10. Grant P, Ayuk J, Bouloux PM, Cohen M, Cranston I,
Murray RD, et al. The diagnosis and management of inpatient
hyponatraemia and SIADH. Eur J Clin Invest 2015;45:888-94.
11. Bruining DM, van Roon EN, de Graaf H, Hoogendoorn M.
Cyclophosphamide-induced symptomatic hyponatraemia.
Neth J Med 2011;69:192-5.
12. Baker M, Markman M, Niu J. Cyclophosphamide-induced
severe acute hyponatremic encephalopathy in patients
with breast cancer: Report of two cases. Case Rep Oncol
2014;7:550-4.
13. Elazzazy S, Mohamed AE, Gulied A. Cyclophosphamide-
induced symptomatic hyponatremia, a rare but severe side
effect: A case report. Onco Targets Ther 2014;7:1641-5.
14. Esposito P, Domenech MV, Serpieri N, Calatroni M, Massa I,
AvellaA, et al. Severe cyclophosphamide-related hyponatremia
in a patient with acute glomerulonephritis. World J Nephrol
2017;6:217-20.
15. Ito R, Hiraga J, Suzuki N, Takagi Y, Kurata H, Kagami Y.
Successful treatment with desmopressin in a case of severe
hyponatremia induced by high-dose cyclophosphamide. Open
J Case Reports Med 2019;1:104.
16. National Cancer Institute Common Terminology Criteria
for Adverse Events (CTCAE) v5.0. Available from: https://
www.ctep.cancer.gov/protocolDevelopment/electronic_
applications/ctc.htm. [Last accessed on 2018 Nov 08].
How to cite this article: Hiraga J, Harada Y, Suzuki N,
Uematsu N, Kagami Y. Hyponatremia Caused by
Cyclophosphamide-containing Chemotherapy for
Malignant Lymphoma Patients: A Single-center and
Retrospective Study. Clin Res Hematol 2020;3(1):8-11.